AURKA induces EMT by regulating histone modification through Wnt/β-catenin and PI3K/Akt signaling pathway in gastric cancer
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Xi Liu1, Zhaoxia Li1, Yue Song1, Rui Wang1, Lei Han3, Qixue Wang2,3, Kui Jiang1, Chunsheng Kang2,3, Qingyu Zhang1
1Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, China
2Department of Neurosurgery, Tianjin Medical University General Hospital, Heping District, Tianjin 300052, China
3Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China
Qingyu Zhang, e-mail: [email protected]
Chunsheng Kang, e-mail: [email protected]
Keywords: AURKA, Wnt/β-catenin pathway, PI3K/Akt pathway, histone modification
Received: November 11, 2015 Accepted: March 28, 2016 Published: April 21, 2016
Gastric cancer, a highly invasive and aggressive malignancy, is the third leading cause of death from cancer worldwide. Genetic association studies have successfully revealed several important genes consistently associated with gastric cancer to date. However, these robust gastric cancer-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. In the present study, we performed an alternative approach, a gene expression-based genome-wide association study (eGWAS) across 13 independent microarray experiments (including 251 gastric cancer cases and 428 controls), to identify top candidates (p<0.00001). Additionally, we conducted gene ontology analysis, pathway analysis and network analysis and identified aurora kinase A (AURKA) as our candidate. We observed that MLN8237, which is a specific inhibitor of AURKA, decreased the β-catenin and the phosphorylation of Akt1 and GSK-3β, as well as blocked the Akt and Wnt signaling pathways. Furthermore, MLN8237 arrested the cells in the G2/M phase. The activity of Wnt and Akt signaling pathways affected the level of histone methylation significantly, and we supposed that MLN8237 affected the level of histone methylation through these two signaling pathways. Additionally, the treatment of MLN8237 influenced the level of H3K4 me1/2/3 and H3K27 me1/2/3. Chip data on cell lines suggested that MLN8237 increases the level of H3K27 me3 on the promoter of Twist and inhibits EMT (epithelial-mesenchymal transition). In summary, AURKA is a potential therapeutic target in gastric cancer and induces EMT through histone methylation.
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